Chromatin remodeling in DNA repair and replication

The genetic information encoded in enormous length of DNA is packaged and compartmentalized into the nucleus of eukaryotes as chromatin. Chromatin consists of nucleosomes as the fundamental unit, where ~146 bp of DNA is wrapped around an octamer of histones in nearly two superhelical turns. Within the histone octamer, two copies of H2A-H2B and H3-H4 dimer pairs form the core histones, whereas, histone H1, also called as linker histone, locks the DNA at the either end of the nucleosome and, along with other architectural proteins, folds the chromatin into more condensed and yet poorly defined higher order structures (see Chap. 1). In almost all nuclear processes involving DNA as a substrate, such as transcription, replication, recombination, and repair, the packaging of the genome in chromatin presents inherent barriers that restrict the access of DNA to processing enzymes. Therefore, to access DNA within a chromatin context, the chromatin is reversibly and locally unfolded by counteracting these chromatin constraints during the nuclear process and refolded back after the process is completed. In this regard, the eukaryotic cell has developed two fundamental chromatin modification strategies that includes: (1) Covalent modification of histones catalyzed by histone-modifying enzyme complexes and (2) ATP-dependent perturbations of histone-DNA interactions catalyzed by the SWI/SNF family of ATP-dependent chromatin remodeling complexes. The covalent modification of histone residues that primarily occurs at the N-terminal region of histones can disrupt histone interaction with DNA or alternatively serve as the binding sites for chromatin-associated factors (Jenuwein and Allis 2001). However, the mechanism employed by ATP-dependent chromatin remodeling complexes uses the energy of ATP hydrolysis to alter the positions or composition of nucleosomes in chromatin (Eberharter and Becker 2004). Much of what we currently know about the biological roles of these two classes of chromatin-modifying factors has come from research on the transcriptional regulatory mechanisms that occur during gene activation, whereas studies from the past decade have also shown the link between chromatin modifications and other nuclear events such as DNA repair and replication. Both covalent modification of histones and ATP-dependent chromatin remodeling have been shown to maintain genome integrity and transmit the genetic and epigenetic information to the next generation. This chapter elaborates how the ATP-dependent chromatin remodeling complexes employ mechanisms that work in concert with the DNA repair and replication processes.